4e20 - Revision history

OCA at 11:01, 1 March 2024

2024-03-01T11:01:21Z

← Older revision		Revision as of 11:01, 1 March 2024
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	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4e20]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E20 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4E20 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4e20]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E20 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4E20 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0MY:N-[4-(3-AMINO-1H-INDAZOL-5-YL)PHENYL]-3-CHLOROBENZENESULFONAMIDE'>0MY</scene></td></tr>		</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.6Å</td></tr>
			<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0MY:N-[4-(3-AMINO-1H-INDAZOL-5-YL)PHENYL]-3-CHLOROBENZENESULFONAMIDE'>0MY</scene></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4e20 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e20 OCA], [https://pdbe.org/4e20 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4e20 RCSB], [https://www.ebi.ac.uk/pdbsum/4e20 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4e20 ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4e20 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e20 OCA], [https://pdbe.org/4e20 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4e20 RCSB], [https://www.ebi.ac.uk/pdbsum/4e20 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4e20 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[[https://www.uniprot.org/uniprot/TYK2_MOUSE TYK2_MOUSE]] Involved in intracellular signal transduction by amplifying type I and type II IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain. Plays an essential role in promoting selective immune responses, including innate host defense mechanisms and specific antiviral activities.		[https://www.uniprot.org/uniprot/TYK2_MOUSE TYK2_MOUSE] Involved in intracellular signal transduction by amplifying type I and type II IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain. Plays an essential role in promoting selective immune responses, including innate host defense mechanisms and specific antiviral activities.
	~~<div style="background-color:#fffaf0;">~~
	~~== Publication Abstract from PubMed ==~~
	ABSTRACT: BACKGROUND: Structure-based drug design (SBDD) can accelerate inhibitor lead design and optimization, and efficient methods including protein purification, characterization, crystallization, and high-resolution diffraction are all needed for rapid, iterative structure determination. Janus kinases are important targets that are amenable to structure-based drug design. Here we present the first mouse Tyk2 crystal structures, which are complexed to 3-aminoindazole compounds. RESULTS: A comprehensive construct design effort included N- and C-terminal variations, kinase-inactive mutations, and multiple species orthologs. High-throughput cloning and expression methods were coupled with an abbreviated purification protocol to optimize protein solubility and stability. In total, 50 Tyk2 constructs were generated. Many displayed poor expression, inadequate solubility, or incomplete affinity tag processing. One kinase-inactive murine Tyk2 construct, complexed with an ATP-competitive 3-aminoindazole inhibitor, provided crystals that diffracted to 2.5--2.6 A resolution. This structure revealed initial "hot-spot" regions for SBDD, and provided a robust platform for ligand soaking experiments. Compared to previously reported human Tyk2 inhibitor crystal structures (Chrencik et al. (2010) J Mol Biol 400:413), our structures revealed a key difference in the glycine-rich loop conformation that is induced by the inhibitor. Ligand binding also conferred resistance to proteolytic degradation by thermolysin. As crystals could not be obtained with the unliganded enzyme, this enhanced stability is likely important for successful crystallization and inhibitor soaking methods. CONCLUSIONS: Practical criteria for construct performance and prioritization, the optimization of purification protocols to enhance protein yields and stability, and use of high-throughput construct exploration enable structure determination methods early in the drug discovery process. Additionally, specific ligands stabilize Tyk2 protein and may thereby enable crystallization.

	Enabling structure-based drug design of Tyk2 through co-crystallization with a stabilizing aminoindazole inhibitor.,Argiriadi MA, Goedken ER, Banach D, Borhani DW, Burchat A, Dixon RW, Marcotte D, Overmeyer G, Pivorunas V, Sadhukhan R, Sousa S, Moore NS, Tomlinson M, Voss J, Wang L, Wishart N, Woller K, Talanian RV BMC Struct Biol. 2012 Sep 20;12(1):22. PMID:22995073<ref>PMID:22995073</ref>

	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~
	~~</div>~~
	~~<div class="pdbe-citations 4e20" style="background-color:#fffaf0;"></div>~~

	==See Also==		==See Also==
	*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]		*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]
	~~== References ==~~
	~~<references/>~~
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 06:45, 28 September 2022

2022-09-28T06:45:42Z

← Older revision		Revision as of 06:45, 28 September 2022
Line 1:		Line 1:

	==Structure of mouse Tyk-2 complexed to a 3-aminoindazole inhibitor==		==Structure of mouse Tyk-2 complexed to a 3-aminoindazole inhibitor==
	<StructureSection load='4e20' size='340' side='right' caption='[[4e20]], [[Resolution\|resolution]] 2.60Å' scene=''>		<StructureSection load='4e20' size='340' side='right'caption='[[4e20]], [[Resolution\|resolution]] 2.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4e20]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Lk3_transgenic_mice Lk3 transgenic mice~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E20 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4E20 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4e20]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E20 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4E20 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0MY:N-[4-(3-AMINO-1H-INDAZOL-5-YL)PHENYL]-3-CHLOROBENZENESULFONAMIDE'>0MY</scene~~></td></tr>~~		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0MY:N-[4-(3-AMINO-1H-INDAZOL-5-YL)PHENYL]-3-CHLOROBENZENESULFONAMIDE'>0MY</scene></td></tr>
	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4e1z\|4e1z]]</td></tr>~~		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4e20 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e20 OCA], [https://pdbe.org/4e20 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4e20 RCSB], [https://www.ebi.ac.uk/pdbsum/4e20 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4e20 ProSAT]</span></td></tr>
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">Tyk2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4e20 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e20 OCA], [~~http~~://pdbe.org/4e20 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4e20 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4e20 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4e20 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[[~~http~~://www.uniprot.org/uniprot/TYK2_MOUSE TYK2_MOUSE]] Involved in intracellular signal transduction by amplifying type I and type II IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain. Plays an essential role in promoting selective immune responses, including innate host defense mechanisms and specific antiviral activities.		[[https://www.uniprot.org/uniprot/TYK2_MOUSE TYK2_MOUSE]] Involved in intracellular signal transduction by amplifying type I and type II IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain. Plays an essential role in promoting selective immune responses, including innate host defense mechanisms and specific antiviral activities.
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 23:		Line 20:

	==See Also==		==See Also==
	*[[Tyrosine kinase\|Tyrosine kinase]]		*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Lk3 transgenic mice~~]]		[[Category: Large Structures]]
	[[Category: ~~Non-specific protein-tyrosine kinase~~]]		[[Category: Mus musculus]]
	[[Category: Argiriadi~~, M A~~]]		[[Category: Argiriadi MA]]
	[[Category: Borhani~~, D W~~]]		[[Category: Borhani DW]]
	[[Category: Talanian~~, R V]]~~		[[Category: Talanian RV]]
	~~[[Category: Kinase]]~~
	~~[[Category: Kinase catalytic domain]]~~
	~~[[Category: Transferase-transferase inhibitor complex~~]]

OCA at 12:39, 11 August 2016

2016-08-11T12:39:01Z

← Older revision		Revision as of 12:39, 11 August 2016
Line 1:		Line 1:

	==Structure of mouse Tyk-2 complexed to a 3-aminoindazole inhibitor==		==Structure of mouse Tyk-2 complexed to a 3-aminoindazole inhibitor==
	<StructureSection load='4e20' size='340' side='right' caption='[[4e20]], [[Resolution\|resolution]] 2.60Å' scene=''>		<StructureSection load='4e20' size='340' side='right' caption='[[4e20]], [[Resolution\|resolution]] 2.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4e20]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Mus_musculus Mus musculus~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E20 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4E20 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4e20]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E20 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4E20 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0MY:N-[4-(3-AMINO-1H-INDAZOL-5-YL)PHENYL]-3-CHLOROBENZENESULFONAMIDE'>0MY</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0MY:N-[4-(3-AMINO-1H-INDAZOL-5-YL)PHENYL]-3-CHLOROBENZENESULFONAMIDE'>0MY</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4e1z\|4e1z]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4e1z\|4e1z]]</td></tr>
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">Tyk2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 ~~Mus musculus~~])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">Tyk2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4e20 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e20 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4e20 RCSB], [http://www.ebi.ac.uk/pdbsum/4e20 PDBsum]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4e20 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e20 OCA], [http://pdbe.org/4e20 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4e20 RCSB], [http://www.ebi.ac.uk/pdbsum/4e20 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4e20 ProSAT]</span></td></tr>
	</table>		</table>
			== Function ==
			[[http://www.uniprot.org/uniprot/TYK2_MOUSE TYK2_MOUSE]] Involved in intracellular signal transduction by amplifying type I and type II IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain. Plays an essential role in promoting selective immune responses, including innate host defense mechanisms and specific antiviral activities.
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 17:		Line 20:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
			<div class="pdbe-citations 4e20" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
	*[[Janus kinase\|Janus kinase]]
	*[[Tyrosine kinase\|Tyrosine kinase]]		*[[Tyrosine kinase\|Tyrosine kinase]]
	== References ==		== References ==
Line 25:		Line 28:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Mus musculus~~]]		[[Category: Lk3 transgenic mice]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Argiriadi, M A]]		[[Category: Argiriadi, M A]]

OCA at 12:37, 5 January 2015

2015-01-05T12:37:45Z

← Older revision		Revision as of 12:37, 5 January 2015
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4e20]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E20 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4E20 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4e20]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E20 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4E20 FirstGlance]. <br>
	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0MY:N-[4-(3-AMINO-1H-INDAZOL-5-YL)PHENYL]-3-CHLOROBENZENESULFONAMIDE'>0MY</scene><br>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0MY:N-[4-(3-AMINO-1H-INDAZOL-5-YL)PHENYL]-3-CHLOROBENZENESULFONAMIDE'>0MY</scene></td></tr>
	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4e1z\|4e1z]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4e1z\|4e1z]]</td></tr>
	<tr><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">Tyk2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 Mus musculus])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">Tyk2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 Mus musculus])</td></tr>
	<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>
	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4e20 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e20 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4e20 RCSB], [http://www.ebi.ac.uk/pdbsum/4e20 PDBsum]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4e20 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e20 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4e20 RCSB], [http://www.ebi.ac.uk/pdbsum/4e20 PDBsum]</span></td></tr>
	<table>		</table>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 27:		Line 27:
	[[Category: Mus musculus]]		[[Category: Mus musculus]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Argiriadi, M A.]]		[[Category: Argiriadi, M A]]
	[[Category: Borhani, D W.]]		[[Category: Borhani, D W]]
	[[Category: Talanian, R V.]]		[[Category: Talanian, R V]]
	[[Category: Kinase]]		[[Category: Kinase]]
	[[Category: Kinase catalytic domain]]		[[Category: Kinase catalytic domain]]
	[[Category: Transferase-transferase inhibitor complex]]		[[Category: Transferase-transferase inhibitor complex]]

OCA at 07:44, 9 July 2014

2014-07-09T07:44:34Z

← Older revision		Revision as of 07:44, 9 July 2014
Line 1:		Line 1:
	[[~~Image~~:~~4e20~~.~~jpg~~\|~~left~~\|~~200px~~]]		==Structure of mouse Tyk-2 complexed to a 3-aminoindazole inhibitor==
			<StructureSection load='4e20' size='340' side='right' caption='[[4e20]], [[Resolution\|resolution]] 2.60Å' scene=''>
			== Structural highlights ==
			<table><tr><td colspan='2'>[[4e20]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E20 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4E20 FirstGlance]. <br>
			</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0MY:N-[4-(3-AMINO-1H-INDAZOL-5-YL)PHENYL]-3-CHLOROBENZENESULFONAMIDE'>0MY</scene><br>
			<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4e1z\|4e1z]]</td></tr>
			<tr><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">Tyk2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 Mus musculus])</td></tr>
			<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>
			<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4e20 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e20 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4e20 RCSB], [http://www.ebi.ac.uk/pdbsum/4e20 PDBsum]</span></td></tr>
			<table>
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			ABSTRACT: BACKGROUND: Structure-based drug design (SBDD) can accelerate inhibitor lead design and optimization, and efficient methods including protein purification, characterization, crystallization, and high-resolution diffraction are all needed for rapid, iterative structure determination. Janus kinases are important targets that are amenable to structure-based drug design. Here we present the first mouse Tyk2 crystal structures, which are complexed to 3-aminoindazole compounds. RESULTS: A comprehensive construct design effort included N- and C-terminal variations, kinase-inactive mutations, and multiple species orthologs. High-throughput cloning and expression methods were coupled with an abbreviated purification protocol to optimize protein solubility and stability. In total, 50 Tyk2 constructs were generated. Many displayed poor expression, inadequate solubility, or incomplete affinity tag processing. One kinase-inactive murine Tyk2 construct, complexed with an ATP-competitive 3-aminoindazole inhibitor, provided crystals that diffracted to 2.5--2.6 A resolution. This structure revealed initial "hot-spot" regions for SBDD, and provided a robust platform for ligand soaking experiments. Compared to previously reported human Tyk2 inhibitor crystal structures (Chrencik et al. (2010) J Mol Biol 400:413), our structures revealed a key difference in the glycine-rich loop conformation that is induced by the inhibitor. Ligand binding also conferred resistance to proteolytic degradation by thermolysin. As crystals could not be obtained with the unliganded enzyme, this enhanced stability is likely important for successful crystallization and inhibitor soaking methods. CONCLUSIONS: Practical criteria for construct performance and prioritization, the optimization of purification protocols to enhance protein yields and stability, and use of high-throughput construct exploration enable structure determination methods early in the drug discovery process. Additionally, specific ligands stabilize Tyk2 protein and may thereby enable crystallization.

	~~{{STRUCTURE_4e20\| PDB=4e20 \| SCENE= }}~~		Enabling structure-based drug design of Tyk2 through co-crystallization with a stabilizing aminoindazole inhibitor.,Argiriadi MA, Goedken ER, Banach D, Borhani DW, Burchat A, Dixon RW, Marcotte D, Overmeyer G, Pivorunas V, Sadhukhan R, Sousa S, Moore NS, Tomlinson M, Voss J, Wang L, Wishart N, Woller K, Talanian RV BMC Struct Biol. 2012 Sep 20;12(1):22. PMID:22995073<ref>PMID:22995073</ref>

	~~===Structure~~ of ~~mouse Tyk-2 complexed to a 3-aminoindazole inhibitor===~~		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
			</div>

	~~{{ABSTRACT_PUBMED_22995073}}~~		==See Also==
			*[[Janus kinase\|Janus kinase]]
	==~~About this Structure~~==		*[[Tyrosine kinase\|Tyrosine kinase]]
	[[~~4e20~~]] ~~is a 1 chain structure with sequence from~~ [~~http://en.wikipedia.org/wiki/Mus_musculus Mus musculus~~]~~. Full crystallographic information is available from [http:~~//~~oca.weizmann.ac.il/oca-bin/ocashort?id=4E20 OCA].~~		== References ==
			<references/>
			__TOC__
			</StructureSection>
	[[Category: Mus musculus]]		[[Category: Mus musculus]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]

OCA at 06:08, 3 October 2012

2012-10-03T06:08:08Z

← Older revision		Revision as of 06:08, 3 October 2012
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	~~'''Unreleased structure'''~~		[[Image:4e20.jpg\|left\|200px]]

	~~The entry~~ 4e20 ~~is ON HOLD~~ ~~until Paper Publication~~		{{STRUCTURE_4e20\| PDB=4e20 \| SCENE= }}

	~~Authors: Argiriadi, M.A., Talanian, R.V., Borhani, D.W.~~		===Structure of mouse Tyk-2 complexed to a 3-aminoindazole inhibitor===

	~~Description~~: ~~Structure of mouse Tyk~~-~~2 complexed to a 3~~-~~aminoindazole~~ inhibitor		{{ABSTRACT_PUBMED_22995073}}

			==About this Structure==
			[[4e20]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E20 OCA].
			[[Category: Mus musculus]]
			[[Category: Non-specific protein-tyrosine kinase]]
			[[Category: Argiriadi, M A.]]
			[[Category: Borhani, D W.]]
			[[Category: Talanian, R V.]]
			[[Category: Kinase]]
			[[Category: Kinase catalytic domain]]
			[[Category: Transferase-transferase inhibitor complex]]

OCA at 07:43, 11 July 2012

2012-07-11T07:43:17Z

← Older revision		Revision as of 07:43, 11 July 2012
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	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 4e20 is ON HOLD		The entry 4e20 is ON HOLD until Paper Publication

	Authors: Argiriadi, M.A., Talanian, R.V., Borhani, D.W.		Authors: Argiriadi, M.A., Talanian, R.V., Borhani, D.W.

	Description: Structure of mouse Tyk-2 complexed to a 3-aminoindazole inhibitor		Description: Structure of mouse Tyk-2 complexed to a 3-aminoindazole inhibitor

OCA at 07:11, 4 July 2012

2012-07-04T07:11:05Z

← Older revision		Revision as of 07:11, 4 July 2012
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	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 4e20 is ON HOLD ~~until Paper Publication~~		The entry 4e20 is ON HOLD

	Authors: Argiriadi, M.A., Talanian, R.V., Borhani, D.W.		Authors: Argiriadi, M.A., Talanian, R.V., Borhani, D.W.

	Description: Structure of mouse Tyk-2 complexed to a 3-aminoindazole inhibitor		Description: Structure of mouse Tyk-2 complexed to a 3-aminoindazole inhibitor

OCA at 07:28, 18 April 2012

2012-04-18T07:28:35Z

← Older revision		Revision as of 07:28, 18 April 2012
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 4e20 is ON HOLD		The entry 4e20 is ON HOLD until Paper Publication

	Authors: Argiriadi, M.A., Talanian, R.V., Borhani, D.W.		Authors: Argiriadi, M.A., Talanian, R.V., Borhani, D.W.

	Description: Structure of mouse Tyk-2 complexed to a 3-aminoindazole inhibitor		Description: Structure of mouse Tyk-2 complexed to a 3-aminoindazole inhibitor

OCA: Protected "4e20" [edit=sysop:move=sysop]

2012-03-14T06:16:35Z

Protected "4e20" [edit=sysop:move=sysop]

← Older revision	Revision as of 06:16, 14 March 2012
(No difference)